There are numerous devices and techniques available for intra-arterial treatment of hepatocellular carcinoma (HCC). Professor Riccardo Lencioni, Division of Diagnostic and Interventional Radiology, Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Italy, presented a critical evaluation of device selection and delivery technique, from the perspective of an interventional radiologist.
He began by outlining the current transarterial therapies: TACE (transarterial chemoembolisation - anticancer drug plus lipiodol and embolising agent); TAE (transarterial embolisation - embolising agent); and TOCE (transarterial oily chemoembolisation - anticancer drug plus lipiodol). A recent paper published by the Royal Free Hospital, London, UK, outlined the breakdown of transarterial therapeutic studies (Marelli et al, CVIR 2007). The analysis found that a total of 75% of studies were concentrated on TACE (45 cohort studies or RCTs), 11% were TAE (seven cohort studies or RCTs) and 11% were TOCE (seven cohort studies or RCTs).
Given the variety of transarterial therapies, Lencioni identified seven inherent variables that should be evaluated when deciding which technique to choose. These are: anticancer drug(s), dosage of chemotherapeutic agent, treatment schedule, use of lipiodol, embolising agent, delivery and timing, and selectivity (amount of liver embolised).
Anticancer drug
Again, citing the study by Marelli et al, Lencioni said that over the years nearly half of all the studies (39 studies, 75%) have used either doxorubicin/epirubicin (48%) as anticancer drug in TACE. However, a third of studies have used cisplatin (31%), with the remainder using mitomycin C (8%) or another (13%).
In addition, some studies have been identified that have used double or triple therapy (11 studies, 21%) of doxorubicin/epirubicin + cisplatin/mitomycin C. The sources of evidence are limited, with only three randomised controlled trials (RCTs) assessing doxorubicin versus epirubicin/cisplatin and only one RCT assessing cisplatin versus cisplatin + epirubicin. Therefore, in regard to anticancer drugs, Lencioni concluded that there is no evidence of the superiority of any anticancer agent alone or of monotherapy versus combination therapy.
Treatment schedule
Surprisingly, of the reported case series, there are no RCTs that have assessed the schedule for treating HCC. Nearly half of the studies (48 studies, 47%) identified by Marelli et al, did not even report the treatment schedules. Given the importance of treatment scheduling as a major determinant of response, Lencioni commented that this was a surprising discovery. Of the remaining studies (45 studies, 53%), there were two treatment strategies: a fixed time interval (4-12 wks, 34 studies, 33%), which highlighted a great variation in the times given; or treatment on demand (20 studies, 20%), based on information from imaging. Therefore, Lencioni concluded that the best treatment schedule remains unknown.
Use of lipiodol
Lipiodol is the oldest constrast agent used, and is an iodinated, radio-opaque constrast material, and was originally used for non-vascular procedures. It is claimed that lipiodol is not truly an embolic agent, and that it slows down the the circulation facilitating the distribution of the emulsion inside the tumour. However, Lencioni pointed out that the emulsion that is manually created is rather unstable, and asked whether lipiodol becomes water-in-oil or oil-in-water. This could have a major effect on the exposure of the chemotherapeutic agent on the cells.
This was demonstrated by Johnson et al, J Hepatol 1991. One group of patients was injected with intra-arterial doxorubicin and the other doxorubicin plus lipiodol. There were no differences identified in the plasmatic level of doxorubicin (Figure 1). He added that the statement that lipiodol offers a sustained localised delivery has been overestimated, and quoted the conclusion of Marelli et al. - "Although lipiodol has been widely adopted in TACE protocols, its efficacy has not been proven. In particular, there are no data showing that lipiodol is able to release chemotherapeutic agents slowly into neoplastic tissue."
Embolising agents
In reporting the use of embolising agents, Lencioni highlighted that the majority of cases report the use of gelatin sponge particles (71%), although some 11% of cases failed to report which embolising agent they used (Marelli et al, CVIR 2007). Of the reported series concerning gelatin sponge, more than a quarter (27%) failed to report which type of gelatin formula they used. The cases that did report the formula type of gelatin sponge used differ considerably (cubes, 14% - pellets, 11% - powder, 8% - fragments, 5% and strips, 5%), and therefore the size of the particles and their ability to embolise the tumour make it difficult to come to any conclusions with regard to appropriate size and formula type.
DEB and TACE
Drug-Eluting Beads (DEB) do, however, have several advantages over other embolising agents. This embolic microsphere has the ability to actively sequester doxorubicin from solution and release it in a controlled and sustained fashion.
One advantage is that the preparation is standardised, reducing the risk of contamination. In addition, it is also possible to select the appropriate size and this also allows the operator to determine the size of the beads and the amount of doxorubicin they wish to administer. In addition, different size particles can be utilised in the same procedure, if the operator wishes to achieve different goals of a high concentration of the drug at the tumour vessels (Figure 2) on the one hand, and on the other hand achieve embolisation with the larger beads.
Citing data from Hong et al. Clin Cancer Res 2006, Lencioni showed how higher concentrations of doxorubicin can be delivered to tumours with DEB. In addition, serum doxorubicin levels remain low (Figure 3) when compared to conventional TACE (cTACE) due to the very limited systemic distribution of the drug (Varela et al, BCLC, J Hepatol 2007).
Conclusion
In conclusion, Lencioni said that TACE is a procedure that includes a variety of different approaches and treatment protocols. All these techniques and protocols do affect the result of the procedure from a clinical point of view. Although the use of a doxorubicin-lipiodol emulsion followed by arterial embolisation with gelatine sponge particles is still the most popular technique, it has inherent limitations with regard to standardisation and reproducibility.
From the clinical studies so far, DEB-TACE offers distinct advantages over conventional TACE in terms of a standardised technique, a well-defined bead size and drug dosage, a higher drug concentration into tumour, sustained drug delivery and minimal systemic exposure. Combining the pharmacokinetic profile and the technical advantages, with the response rate and safety profile, DEB should now be considered the standard way of performing TACE.
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